This application addresses broad Challenge Area (15) Translational Science, and specific Challenge Topic, 15- RR-101* Applied Translational Technology Development. Mechanical ventilation is a life support procedure that is indicated for a wide variety of acute or chronic respiratory failure conditions. A major technological challenge facing mechanical ventilation in awake patients with spontaneous breathing activity is how to synchronize the ventilator rhythm with the patient's breathing effort smoothly and effectively. Dyssynchrony could lead to patient discomfort, increased work of breathing and risk of barotrauma, as well as decreases in pulmonary gas exchange efficiency and in cardiac output. Current generation of mechanical ventilators either control the breathing rhythm completely independent of the patient (ventilator-based ventilation), or let the patient trigger the ventilator breath by breath (patient-based ventilation). Neither approach is optimal. We propose a new mode of mechanical ventilation (entrainment-based mechanical ventilation, EMV) that is based on the classical physics theory of mutual entrainment between coupled oscillators, which may provide a cost- effective solution to the problem of patient-ventilator synchrony. This novel technique is motivated by our recent discovery that the brain circuits that control breathing are capable of entraining to a ventilator and adapting to it through learning and memory of the vagally-mediated Hering-Breuer inflation reflex. In EMV, the patient's spontaneous rhythm and the ventilator rhythm are phase-locked to one another on the same tempo, just like two individuals dancing together. The goal of this RC1 project is to transition the base technology from animal studies in the laboratory into the clinic, by first building and bench-testing a prototype of EMV that is suitable for clinical testing (Aim 1) and then carrying out a clinical trial to evaluate its safety and efficacy in comparison with other mechanical ventilation modes such as pressure support ventilation and proportional assist ventilation (Aim 2). Toward this goal, an interdisciplinary research team comprised of a basic researcher/ bioengineer (the PI), a clinician (Co-PI) and a technology developer (Covidien/Puritan-Bennett) has been formed to address the underlying scientific, engineering and clinical problems. Our primary goal is to verify that EMV can be delivered safely and is well tolerated by patients. Secondly, in comparison with pressure support ventilation and proportional assist ventilation we anticipate that entrainment-based ventilation will be: 1) less dependent on patient triggering, hence minimizing the work of breathing: 2) more robust to variabilities of respiratory mechanical parameters and thus should be more stable;3) more cost-effective in that it does not require sophisticated servo mechanisms to control the instantaneous ventilator pressure. The results will provide valuable insights for further development and optimization of the EMV mode in order to maximize patient-ventilator synchrony in a cost-effective manner, and will lay the groundwork for large-scale clinical testing of its efficacy in comparison with other modes of mechanical ventilation in future. Mechanical ventilation is a basic life support procedure that is integral to any intensive care unit, emergency room, ambulatory unit or ventilator weaning facility, and is ubiquitous in many medical units and rehabilitation or long-term care facilities, including the patient's own home. PUBLIC HEALTH RELEVANCE: A major longstanding problem in delivering mechanical ventilation to patients who can still breathe on their own to some extent is how to synchronize the ventilator rhythm to the patient's spontaneous breathing rhythm so they do not "fight" each other to cause hazards. This project will evolve a novel mechanical ventilation technique called "entrainment-based mechanical ventilation" which will provide a safe and cost-effective solution to this clinical problem.